Tryptamines

ABSTRACT

Substituted indoles and benzimidazoles having serotonin blocking activity and having the structural formulae   and   wherein one and only one of Y or Z is -OR3 and WHEREIN R1, R2 and R3 is H or lower alkyl, and WHEREIN R4 is a phenyl group or phenyl group substituted with lower alkyl, lower alkoxy, halogen, CF3, NH2, NO2, CN, -NH-lower alkyl or   GROUP.

United States Patent [191 Smythies [54] TRYPTAMINES 75] Inventor: John R. Smythies, Birmingham, Ala.

[73] Assignee: Nelson Research & Development Co., Irvine, Calif.

[22] Filed: Feb. 11, 1974 [21] Appl. No.: 441,299

Related U.S. Application Data [63] Continuation-impart of Ser. No. 340,698, March 13,

1973, abandoned.

52 US. Cl. 260/326.l5; 260/296 A; 260/3092; 260/326.13 R; 260/326.16; 260/326.31;

51 Int. c1. c071) 209/16 58 Field of Search 260/326.15; 340/698 Primary ExaminerSherman D. Winters Attorney, Agent, or Firm-Martin A. Voet [57 ABSTRACT Substituted indoles and benzimidazoles having serotonin blocking activity and having the structural formulae [ Oct. 28, 1975 and (DI E Ch -R wherein one and only one of Y or Z is -OR and wherein R R and R is H or lower alkyl, and wherein R is a phenyl group or phenyl group substituted with lower alkyl, lower alkoxy, halogen, CF NI-I N0 CN, Nl-I-lower alkyl or lower alkyl -N group.

\ lower alkyl 7 Claims, No Drawings TRYPTAMINES RELATION TO EARLIER FILED APPLICATIONS This application is a Continuation-in-part of US. Ser. No. 340,698 filed Mar. 13, 1973, now abandoned.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The present invention comprises a compound having serotonin blocking activity and having one of the following structural formulae R1 CHZCHZN/ Y R, FORMULA A R, FORMULA B in which one and only one of Y or Z is OR and in which each of R R and R is H or a lower alkyl group having 1 to about 8 carbon atoms and preferably an alkyl group containing not more than 5 carbon atoms, particulary methyl, ethyl or propyl; and R is an unsubstituted or substituted phenyl group of the formula in which n is 0-5 and X is H, a lower alkyl or lower alkoxy group having 1 to about 8 carbon atoms, halogen, CF NH N0 CN, NH-lower alkyl, or

lower alkyl -NH lower alkyl DETAILED DESCRIPTION OF THE INVENTION The compound shown in formula B, a substituted benzimidazole, may have the group R O-- in the 6- position. It is, however, to be understood that the com- 2 tion may also include conventional pharmaceutically acceptable carriers and diluents.

The foregoing compounds, particularly those in which R,, R and R are members of the group consisting of hydrogen and C alkyl groups may act to hinder or prevent the interaction of basic brain protein (of Myelin) and all mediated immune responses to this protein which occurs in demyelinating conditions such as multiple sclerosis. Thecompounds may also be usepounds in which the group R 0 is in the 5-position are also included in the invention.

It will be understood that the compounds of formulae A and B may be in the form of conventional pharmaceutically acceptable acid addition salts. The composiful in the treatment of cancer since lymphocytes of patients with cancer will react with basic brain protein immunologically and this reaction is prevented by serotonin.

Furthermore, these compounds have been shown to be inhibitors of serotonin reuptake in the brain thereby increasing neurotransmission across synapses where serotonin is the native transmitter substance. In addition, these compounds have been shown to potentiate REM (rapid eye movement) sleep in cats and therefore may have beneficial qualities as sleep inducing agents.

The invention also includes a method of treating an animal (including human beings) with a composition comprising at least one of the compounds of formulae A and B as such or in the form of its pharmaceutically acceptable acid addition salt, for example, the hydrochloride. The composition may be introduced into the body by any one of the routes conventionally employed for introducing a drug into the body. Thus, for example, the composition may be administered orally, topically or parenterally, at a dose range ofO. 1-100 mg/Kg. More particularly the compounds of the invention are generally characterized by the pharmacological activity hereinbefore stated, making them useful in counteracting certain physiological abnormalities in a living animal body. Effective quantities of the pharmacologically active compounds of the invention may be administered to a living animal body in any one of various ways, for example orally as in capsules or tablets, or parenterally in the form of sterile solutions, suspensions, or by pellet implantation. Among possible routes of parenteral administration are intravenously, subcutaneously, intrarnuscularly and intraperitoneally. Other modes of administration are lingually, vaginally, by aerosol and topically as e.g. in the form of ointments, eyedrops etc.

As representative of living animal bodies, which may be treated with the compounds and compositions of the invention, and according to the method of treating of the invention, for alleviation of the same and/or similar conditions as those described, in addition may also be mentioned the following: domestic animals such as dogs and cats, farm animals such as horses, cows, sheep and goats.

Pharmaceutical formulations are usually prepared from a predetermined quantity of one or more of the compounds of the invention. Such formulations may take the form of powders, suppositories, ointments, eye-drops, elixirs, solutions, aerosols, pills, capsules, pellets or tablets, suspensions, oil solutions etc., with or without, but preferably with, any one of a large variety of pharmaceutically acceptable vehicles or carriers.

pyrrolidone and lubricants such as sodium stearate, may be used to form tablets. Disintegrating agents'such as sodium bicarbonate may also be included in tablets.

Although relatively small quantities of the active materials of the invention, even as low as 5.0 milligrams may be used in cases of administration to'subjects having arelatively low body weight, unit dosages arepreferably 5 milligrams or above and preferably 25, 50, or 100 milligrams, or even'higher, depending of course upon the subject treated and the particular result desired, as will be apparent to one skilled in the art. Broader ranges appear'to be 0.1 to 3000 milligrams per unit dose. The active agents of the invention may be combined for administration with other pharmacologically active agents such as natural or synthetic prostaglandins or analogues, antiseptics, spasmolytics, analgesics, tranquillizers, steroids or hormones, or the like,

or with buffers, antacids or the like, and the proportion METHOD I of the active agent of agents in the compositions may Z (1U 1 l COCl Y I N I H II N O H Z c NH HN/ CHFCBHS Y C 2 cl-i -cn-i I ll N H 0 Y 2 cH.-c.,H,

N 0 H l (i) LiAlH,

(ii) HCl (i) LiAll-l, z

. ci-i, c.,l-i

(ii) HCI be varied widely. It is only necessary that the active ingredient of invention constitutes an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to well established medical and/or veterinary principles. As a rule, however, when used therapeutically, the present compounds may be administered in a quantity of 1 to 1000 milligrams per day and patient, divided in 1 to 4 doses, during a period of 1 day to 1 year.

The compounds of formula A may be designated as substituted tryptamines and may be readily produced by one of the following general methods I, II and lIl.

.HCl 1 H lPd Z cu NH .HCl Y cu 2 u, Z R, H Y

I NH N H R METHOD n I METHOD m z /CH-; Z CH I Y CHZOJ-IN H,-

N N H H (i) CH;,I (ii) NaCN Z CHZCN Lian-i Z Y CH2CH2NH2 KIT The final compound can be condensed as in 30 The final compound in method II can also be conmethod with an appropriately Substituted lat-CH0 verted to 2-substituted tryptamine derivatives as shown and the product hydrogenated to obtain the tryptamlne b 61 Ow:

derivative.

0 Z ll 2 Y R -c-cl Y 0.5N NaOH I N NH N NH H H {:0 l 4 R CHCOOH POCI; or any acidic condensing agent 2 H CH 2 N N H Cl- H H R Na/EtOH NHgNH:

KOH HQ Dicthylenc Z glycol Y I NH N H Hg/Pd NH, l N H 4 For example, the compounds of formula A may be hydrochlorides is shown below for purposes of illustramade by reducing a S-hydroxyor 5-alkoxy-, 3-indolyltion. glyoxylamide with lithium aluminum hydride and by hydrogenolysis of substituted l,2,3,4-tetrahydro, ,Bcar- EXAMPLE I boline systems. An example of a typical synthesis of 2- 5 Synthesis of 2-benzyl-5-hydroxyand 2-benzyl-5- benzyl-S-hydroxy-and 2-benzyl-5-methoxy-tryptamine methoxyti yptamine hydrochlorides (XIII and XIV).

I XIII R H XIV R ==CI-I -continued XIII R H XIV R CH;,

S-benzyloxyand 5-methoxy-3indole-glyoxylyl chloride (III and IV).

S-benzyloxy indole (I) in absolute ether when treated with oxalyl chloride at O C gives a quantitative yield of 5-benZyloxy-3-ind0le-glyoxylyl chloride (III). m.p. (lit.) 146150 dec.

Similarly, S-methoxy indole (II) gives a 5-methoxy-3- indoleglyoxylyl chloride (IV).

S-benzyloxyand 5-methoxy-3-indole-N,N-dibenzylglyoxyl amide (V and VI).

The crude acid chloride (III) when added in small portions to dibenzylamine in ether gives a 91% yield of 5-benzyloxy-3-indole-N,N-dibenzylglyoxylamide (V) m.p. (lit.) l5015l.

Similarly, the acid chloride (IV) with dibenzylamine gives 5-methoxy-3-indole-N,N-dibenzylglyoxylamide S-benzyloxyand 5-methoxy-3-(2-dibenzylaminoethyl)-indole hydrochloride. (VII and VIII).

When the amide (V) is suspended in dry benzene and added to lithium aluminum hydride in dry ether and refluxed, it gives the reduced product, 5-benzyloxy-3- (2dibenzylaminoethyl)-indole as the hydrochloride salt in 92% yield (VII) m.p. (lit.) 232233.

Similarly, the amide (VI) gives on treatment with lithium aluminum hydride 5-methoxy-3-(2-dibenzylamino ethyl)-indole (VIII) hydrochloride (VIII).

These hydrochlorides can be converted to the free bases or used as hydrochlorides in the next step (hydrogenolysis). 5hydroxyand S-methQXy-tryptarnine hydrochlorides (IX and X).

5-benzyloxy-3-(2-dibenzylaminoethyl)-indole hydrochloride (VII) in ethanol when hydrogenated with palladium at 35 gives S-hydroxy-tryptamine hydrochloalic acid amide (XVI) gives S-methoxy-tryptamine,

which is isolated as hydrochloride (X), obtained previously also by another route.

l-phenyl-6-hydroxy l,2,3,4-tetrahydro-B-carb0line (XI), l-phenyl-6-methoxy l,2,3,4-tetrahydro-/3-carboline (XII) and l-phenyl-6-benzyloxy l,2,3,4-tetrahydro-B-carboline (XVIII).

5-hydroxy-tryptamine (IX) hydrochloride (IX) undergoes a condensation with benzaldehyde at 60 in the presence of 0.125 N sulfuric acid to give lphenyl-6- hydroxy l,2,3,4-tetrahydro-B-carboline hydrochloride. This on treatment with ammonium hydroxide at 40 for 3 hours gives the free base l-phenyl-6-hydroxy l,2,3,4-tetrahydro-B-carboline (XI) in 85.5% yield.

Similarly, 5-methoxy-tryptamine hydrochloride (X) y and S-benzyloxy-tryptamine hydrochloride (XVII) given l-phenyl-6-methoxy-l ,2,3 ,4-tetrahydro-B-carboline (XII) and l-phenyl-6-benzyloxyl,2,3,4-tetrahydro-B-carboline (XVIII) respectively. 2-benzyl-S-hydrQXy-tryptamine hydrochloride (XIII) and Z-benzyl-S-methoxy-tryptamine hydrochloride (XIV).

l-phenyl-6-hydroxy l,2,3,4-tetrahydro-B-carboline (XI) in acetic acid is hydrogenated with 10% palladium on carbon at under 6 atmospheric pressure of hydrogen until the hydrogen uptake ceases. The free base is obtained by treating with ammonium hydroxide. This is taken in ether and converted with hydrochloric acid gas to 2-benzyl-5-hydroxy-tryptamine hydrochloride (XIII).

In similar way, l-phenyl-6-benzyloxyl,2,3,4-tetrahydro-B-carboline (XVIII) gives also 2-benzyl-5- hydroxy-tryptamine hydrochloride (XIII), whereas, 1- phenyl-6-methoxy- 1 ,2,3,4-tetrahydro-B-carboline (XII) gives 2-benzyl-5-methoxy-tryptamine hydrochloride (XIV).

Compounds having the OR, group in the 4-position rather than the 5-position are made in the same way, except that the starting material has the 0R group substituted at the 4 rather than the 5-position.

The substituted benzimidazoles, that is, the compounds of formula B, may be prepared by the following methods in which the benzimidazole taken as an example is l-(B-amino-ethyl)-2-benzyl-6-methoxybenzimidazole (and the corresponding S-methoxy isomer).

EXAMPLE II 4-methoxy-l 2-phenylenediamine is condensed with benzyl cyanide in the presence of acid to give Z-benzyl- 5(6)-methoxybenzimidazole. This compound is amino alkylated with 2-chloro-ethylamine in the presence of sodium ethylate to yield a mixture of l-( B-aminoethyb- 2-benzyl-5-and o-methoxy-benzimidazoles, which is separated to give the pure 1(B-aminoethyl )-2-benzyl-6- methoxybenzimidazole.

EXAMPLE III 4-methoxy-l,Z-phenylenediamino is heated with phenylacetic acid in the presence of hydrochloric acid to give 2-benzyl-5(6)-methoxybenzimidazole. Aminoalkylation with 2-chlorethylamine to form the mixture of l-( 3-aminoethyl)-2-benzyl-5- and 6-benzimidazoles is carried as in EXAMPLE II, from which the desired 6-methoxy isomer is separated.

EXAMPLE IV The intermediate 2-benzyl-5(6)-methoxybenzimidazole is obtained by warming 4-methoxy-l, 2- phenylenediamine with phenylacetimino methyl ether in the presence of hydrochloric acid. Conversion to the mixed l-(B-aminoethyD-Z-benzyl-S- and 6-methoxybenzimidazoles is accomplished with 2-chloroethylamine as in EXAMPLE II, and these are separated as above.

EXAMPLE V 3-methoxyaniline (m-anisidine) is acylated with phenylacetyl chloride to form 3-methoxyphenylacetanilide. Nitration of this amide yields 2- nitro-5-methoxy-phenylacetanilide which is treated with tin and hydrochloric acid to undergo reductive cyclization to form 2-benzyl-5(6)-methoxy-benzimidazole. Aminoalkylation to a mixture of l-(B- aminoethyl)-2-benzyl-5- and 6-methoxybenzimidazole is accomplished as in EXAMPLE I] and the two isomers are separated.

EXAMPLE VI 3-methoxy-a-phenylacetanilide (described in EX- AMPLE V) is n-alkylated with 2-chlorethylamine in the presence of sodium ethylate to form N-( 2-aminoethyl)-a-3-methoxy-a-phenylacetanilide. That compound is nitrated to give 2-nitro-5-methoxy-N-(B- aminoethyl)-a-phenylacetanilide which on reductive cyclization with tin and hydrochloric acid yields l-(B- aminoethyl)-2-benzyl-6-methoxybenzimidazole directly without the necessity of separating from the 5- methoxy isomer.

EXAMPLE vii As an alternate to the route set forth in EXAMPLE VI, N-( B-aminoethyl )-3-rnethoxy-a-phenylacetanilide, (prepared from the reaction of m-anisidine and 2- chloroethylamine to obtain ,N-(B-aminoethyl)-3- methoxyaniline, the latter being condensed with phenylacetylchloride) is nitrated to give N-(B-aminoethyl)-a-nitro-3-methoxy-aphenyl acetanilide which on reductive cyclization with tin and hydrochloric acid yields 1 B-aminoethyl )-2-benzyl-6-methoxybenzimidazole.

The production of the substituted benzimidazoles in which R, is other than methyl and/or one or both of R and R are alkyl groups and/or one or more of X are other than hydrogen, is within the competence of a person skilled in the art with the knowledge of EXAM- PLES II to VII.

EXAMPLE VIII In Vitro Studies on 2-benzyl-5-methoxy-tryptamine hydrochloride 2-benzyl-5-methoxy-tryptamine hydrochloride was found to cause a weak contraction of the isolated, in vitro, rat fundus similar to that produced by 5-hydroxytryptamine (S-HT), but with a strong binding capability. Dose-response contraction curves were parallel, therefore indicating similar sites and mechanism of action, but a greater than 1000 times concentration of 2- benzyl-S-methoxy-tryptamine hydrochloride was needed to produce the strong response evoked by 5-HT. The compound 2-benzyl-5-methoxytryptamine hydrochloride can act peripherally as a mild 5-HT-like 12 agent and is highly bound to the tissue. 5-HT and 2- benzyl-S-methoxy-tryptamine hydrochloride were found to compete selectively for the same receptors, with Z-benzyl-S-methoxy-tryptamine hydrochloride demonstrating prolonged duration and activity as an inhibitor of 5-HT induced contractions.

In Vivo Studies CNS Interaction with serotonin is evident since 2-benzyl- S-methoxy-tryptamine hydrochloride can reduce the 5-HT depletion caused by a-4-methyl-a-ethylmetatyramine, thus suggesting that 5-HT uptake into the 5-HT terminals can be blocked by 2-benzyl-5- methoxy-tryptamine hydrochloride in doses of 10 to 25 mg/Kg. Also the initial effect of 2-benzyl-5-methoxytryptamine hydrochloride on the 5-HT dependent receptor activity of the extensor hindlimb reflex was seen to be weakly stimulatory, but this response subsided in time, therefore suggesting other possible actions on the 5-HT mechanisms, such as 5-HT receptor blockage. Z-benzyl-S-methOXy-tryptamine hydrochloride was found to be equivalent to chlorimipramine in the mouse serotonin potentiation test.

In vivo tests suggest resistance to the degradative action of monoamine oxidase. 2-benzyl-5-methoxy-tryptamine hydrochloride mg/Kg i.p.) elicited ataxia followed by progressive sedation in mice, which was not enhanced by the monoamine oxidase inhibitor, iproniazid.

sedative-hypnotic effects have been investigated for 2-benzyl-S-methoxy-tryptamine hydrochlorides poten- In Vivo-Miscellaneous The anti-serotonin activity of 2-benzyl-5-methoxytryptamine hydrochloride is further substantiated by the inhibitive effects on serotonin and histamine mediated scald-induced ear edema in mice. In this test 2- benzyl-S-methoxy-tryptamine exhibited on ED of 44 mg/Kg l.p. while that of cyproheptadine was approximately 12 and methylsergide l mg/Kg l.p. (Steriods and methylsergide anti-cholinergics and prostaglandin synthetase inhibitors were inactive.) Serotonin-induced bronchial spasms in anesthetized cats were reduced by 76% by 0.5 mg/Kg doses (I.V.) 2-benzyl-5-methoxytryptamine.

2-benzyl-5-methoxy-tryptamine hydrochloride did not significantly inhibit the Experimental Allergic Encephalomyelitis hindleg paralysis in rats. 2-benzyl-5- methoxy-tryptamine hydrochloride demonstrated a low order of activity in the Passive Cutaneous Anaphylaxis test.

2-benzyl-S-methoxy-tryptamine hydrochloride has been found to be a good inhibitor of lymphocyte migration.

2-benzyl-5-methoxy-tryptamine hydrochloride has demonstratedly blocked the transport of Na and Clin frog skin and human cornea.

I claim:

13 1. A compound having the structural formula CH2CH2N wherein each of R I R and R is selected from the group consisting of H and a lower alkyl group having 1-8 carbon atoms and R is a phenyl group of the formula wherein n is 0-5 and X is selected from the group consisting of H, a lower alkyl group having 1 to 8 carbon atoms, a lower alkoxy group having l-8 carbon atoms, halogen, CF N0 Nl-I CN, NH-lower alkyl,

lower alkyl lower alkyl each X being the same or different or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein n is 0.

3. The hydrochloride acid addition salt of the compound of claim 2.

4. The compound of claim 1 wherein n is l and X is selected from the group consisting of alkyl and alkoxy groups having l-2 carbon atoms.

5. The compound of claim 3 wherein R and R are H' 6. A compound selected from the group consisting of 2-benzyl-4-hydroxy tryptamine and a pharmaceutically acceptable addition salt thereof.

7. A compound selected from the group consisting of 2-benzyl-4-methoxy tryptamine and a pharmaceutically acceptable addition salt thereof. 

1. A COMPOUND HAVING THE STRUCTURAL FORMULA
 2. The compound of claim 1 wherein n is
 0. 3. The hydrochloride acid addition salt of the compound of claim
 2. 4. The compound of claim 1 wherein n is 1 and X is selected from the group consisting of alkyl and alkoxy groups having 1-2 carbon atoms.
 5. The compound of claim 3 wherein R1 and R2 are H.
 6. A compound selected from the group consisting of 2-benzyl-4-hydroxy tryptamine and a pharmaceutically acceptable addition salt thereof.
 7. A compound selected from the group consisting of 2-benzyl-4-methoxy tryptamine and a pharmaceutically acceptable addition salt thereof. 